Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disease that becomes apparent usually in the first year of life, and causes a phenotype resembling many aspects of aging. Affected children have a remarkably similar appearance, despite differing ethnic backgrounds, and die of premature atherosclerosis at an average age of 13 years. Progeria is a disease in which some, but not all, of its clinical manifestations represent a model of accelerated aging (reviewed in Sweeney & Weiss, Gerontology 38:139-52, 1992). Although they are born looking healthy, children with Progeria begin to display many characteristics of accelerated aging at around 18-24 months of age. Clinical features common to progeria and normal aging include alopecia (although the pattern of hair loss differs), sclerodermatosis, atherosclerosis, lipofuscin deposition, nail dystrophy, hypermelanosis, decreased adipose tissue, and osteoporosis.
With the identification of the gene responsible for HGPS, it was determined that HGPS is a type of laminopathy, a group of diseases associated with an underlying defect in the lamin A/C gene (LMNA) (Eriksson et al., Nature 423:293-298, 2003; and U.S. Pat. No. 7,297,492). LMNA codes for the lamin A and lamin C isoforms, which differ due to alternate splicing. The lamins are a component of the nuclear lamina, a fibrous matrix located at the interior of the nuclear membrane, responsible for nuclear integrity and organization (Gruenbaum et al., J Struct Biol 129:313-23, 2000; Gruenbaum et al., Nat. Rev. Mol. Cell. Biol. 6:21-31, 2005).
Nearly all HGPS patients have the same silent mutation (G608G) creating an abnormal splice donor site in exon 11 of the LMNA gene (Eriksson et al., Nature 423:293-298, 2003), which causes a 150 base pair mRNA deletion in the lamin A transcript. The result of the mis-splicing is a protein missing 50 amino acids near the C-terminus (henceforth called “preprogerin” prior to posttranslational processing and “progerin” after post-translational processing). The deleted region includes the protein cleavage site that normally removes the C-terminal 15 amino acids, including a cysteine, which is farnesylated during posttranslational processing. The absence of this proteolytic cleavage site results in a protein which remains farnesylated. Persistently-farnesylated progerin is aberrantly anchored at the inner nuclear membrane and is at least partly responsible for the HGPS cellular phenotypes of nuclear abnormalities and premature apoptosis. Accordingly, it was proposed that inhibition of farnesyltransferase might provide treatment for HGPS (see U.S. Pat. No. 7,297,492). In addition, any abnormality in the lamin A processing pathway can lead to a laminopathy which might benefit from farnesylation or mTOR inhibition.
Promising pre-clinical studies demonstrated the use of farnesyltransferase inhibitors (FTIs) to inhibit and even reverse characteristic HGPS phenotypes of progerin accumulation and nuclear structural abnormalities (see for examples, U.S. Pat. No. 7,838,531 and references cited therein). Similarly, clinical trials of an FTI in HGPS patients demonstrated improvement in several disease aspects, including weight gain, improvements in skeletal rigidity, and improvements in cardiovascular function (Gordon et al., PNAS, 109:16666/16671, 2012).
The clinical trial of FTI treatment in HGPS patients demonstrated some therapeutic benefits of FTI treatment for children with Progeria, but the therapeutic benefit is not complete. Additionally, the increased presence of progerin has been correlated with cardiovascular disease and senescence in non-HGPS subjects (Olive et al., Arterioscler. Thromb. Vasc. Biol., 30:2301-2309, 2010; and McClintock et al., PLoS One, 2:e1269, 2007). Accordingly, a need continues to exist to develop improved treatments for abnormal lamin A-related conditions including HGPS and related laminopathies, abnormal lamin A-related cardiovascular conditions, and other age-related disease.